Over two-thirds of the US population is categorized as overweight or obese. This obesity epidemic is largely driven by the excessive intake of palatable and unhealthy foods. Both the size of an individual meal and the frequency of meal or snack initiation are heavily influenced by previous experience and by exposure to environmental food-associated stimuli (e.g. visual, olfactory) that can override homeostatic mechanisms of feeding. Therefore, the development of effective pharmacological treatments for obesity requires a deeper understanding of the neurobiological systems that integrate previous experience with external cues to control feeding behavior. Preliminary data in this proposal together with recent published work implicate the ventral subregion of the hippocampus (vHP) as a mediator of these higher-order aspects of feeding behavior. The vHP expresses receptors for the gut-derived hormone, ghrelin (GHSR1-As), that when pharmacologically activated, potently increases overall food intake, meal size and frequency, and food-motivated behavior. However, whether ghrelin signaling in the vHP is physiologically relevant for excessive food intake and obesity development is unknown. Furthermore, a comprehensive understanding of the downstream neural substrates involved in vHP ghrelin signaling also requires deeper examination. The primary goals of this proposal are to test the novel hypotheses that chronic down-regulation of ghrelin signaling in the vHP will reduce meal size and frequency, attenuate learned associations between rewarding food and external stimuli, and increase resistance to obesity development (Aim I), as well as to determine the important neural targets and neural circuitry mediating vHP ghrelin signaling (Aim II). To address these hypotheses, experiments in Aim 1 will use localized virogenetic knockdown of GHSR1-As in the vHP in conjunction with novel behavioral paradigms that examine learned associations between the environment and palatable food. Aim II will utilize neuroanatomical, immunohistochemistry methods as well as virogenetic, neuropharmacological, and behavioral techniques to determine the downstream neural targets mediating these hyperphagic effects, focusing on the lateral hypothalamus (LHA) and medial prefrontal cortex (mPFC). Experiments in Aim II will also examine the interaction between vHP ghrelin signaling and reward-related neuropeptidergic systems present in the LHA (orexin) and the mPFC (dopaminergic type-1 receptor signaling).